HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 2, 733-738, January 11, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/2/733    most recent M707103200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yagishita, S. Articles by Ihara, Y. Search for Related Content PubMed PubMed Citation Articles by Yagishita, S. Articles by Ihara, Y. Social Bookmarking                      What's this?

Aβ46 Is Processed to Aβ40 and Aβ43, but Not to Aβ42, in the Low Density Membrane Domains^*

Sosuke Yagishita, Maho Morishima-Kawashima^¶, Shoichi Ishiura, and Yasuo Ihara^||1

From the Department of Neuropathology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, the Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, the ^¶Department of Molecular Neuropathology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, and the ^||Planning Office, Faculty of Life and Medical Sciences, Doshisha University, Kyoto 619-0225, Japan

-Secretase cleaves the transmembrane domain of β-amyloid precursor protein at multiple sites referred to as -, -, and -cleavage sites. We previously showed that N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a potent dipeptide -secretase inhibitor, causes differential accumulation of longer amyloid β-proteins (Aβs) within Chinese hamster ovary cells co-expressing β C-terminal fragment and wild-type presenilin 1 (C99/wtPS1 cells). In this study, we used sucrose density gradient centrifugation to fractionate the membranes from C99/wtPS1 cells that had been pretreated with DAPT. We found that accumulating Aβ46 localized exclusively to low density membrane (LDM) domains. Incubating the Aβ46-accumulating LDM domains at 37 °C produced Aβ40, Aβ42, Aβ43, and β-amyloid precursor protein intracellular domain. The addition of L685,458 completely prevented β-amyloid precursor protein intracellular domain generation and resulted in a large decrease in the level of Aβ46 and the concomitant appearance of Aβ40 and Aβ43 but not Aβ42. Further addition of DAPT suppressed the production of Aβ40/43 and abolished the decrease in the amount of Aβ46. These data indicate that preaccumulated Aβ46 is processed by -secretase to Aβ40/43 but not to Aβ42 in the LDM domains. The amount of newly produced Aβ40 and Aβ43 was roughly equivalent to the decrease in the amount of Aβ46. Temporal profiles did not show a maximal concentration for Aβ43, suggesting that Aβ46 is processed to Aβ40 and Aβ43 through a nonsuccessive process.

Received for publication, August 24, 2007 , and in revised form, November 14, 2007.

^* This work was supported in part by a grant-in-aid for scientific research on priority areas, Research on Pathomechanisms of Brain Disorders (to Y. I.), and a grant-in-aid for science research (C) from the Japan Society for the Promotion of Science (to M. M.-K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Planning Office, Faculty of Life and Medical Sciences, Doshisha University Kai-Fu-Kan, 4-1-1 Kizugawadai, Kizugawa-shi, Kyoto 619-0225, Japan. Tel.: 81-774-73-1920; Fax: 81-774-73-1922; E-mail: yihara{at}mail.doshisha.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Shimojo, N. Sahara, T. Mizoroki, S. Funamoto, M. Morishima-Kawashima, T. Kudo, M. Takeda, Y. Ihara, H. Ichinose, and A. Takashima Enzymatic Characteristics of I213T Mutant Presenilin-1/{gamma}-Secretase in Cell Models and Knock-in Mouse Brains: FAMILIAL ALZHEIMER DISEASE-LINKED MUTATION IMPAIRS {gamma}-SITE CLEAVAGE OF AMYLOID PRECURSOR PROTEIN C-TERMINAL FRAGMENT {beta} J. Biol. Chem., June 13, 2008; 283(24): 16488 - 16496. [Abstract] [Full Text] [PDF]